RNA elements directing in vivo assembly of the 7SK/MePCE/Larp7 transcriptional regulatory snRNP

Through controlling the nuclear level of active positive transcription elongation factor b (P-TEFb), the 7SK small nuclear RNA (snRNA) functions as a key regulator of RNA polymerase II transcription. Together with hexamethylene bisacetamide-inducible proteins 1/2 (HEXIM1/2), the 7SK snRNA sequesters P-TEFb into transcriptionally inactive ribonucleoprotein (RNP). In response to transcriptional stimulation, the 7SK/HEXIM/P-TEFb RNP releases P-TEFb to promote polymerase II-mediated messenger RNA synthesis. Besides transiently associating with HEXIM1/2 and P-TEFb, the 7SK snRNA stably interacts with the La-related protein 7 (Larp7) and the methylphosphate capping enzyme (MePCE). In this study, we used in vivo RNA-protein interaction assays to determine the sequence and structural elements of human 7SK snRNA directing assembly of the 7SK/MePCE/Larp7 core snRNP. MePCE interacts with the short 5'-terminal G1-U4/U106-G111 helix-tail motif and Larp7 binds to the 3'-terminal hairpin and the following U-rich tail of 7SK. The overall RNA structure and some particular nucleotides provide the information for specific binding of MePCE and Larp7. We also demonstrate that binding of Larp7 to 7SK is a prerequisite for in vivo recruitment of P-TEFb, indicating that besides providing stability for 7SK, Larp7 directly participates in P-TEFb regulation. Our results provide further explanation for the frequently observed link between Larp7 mutations and cancer development

A measure of majorisation emerging from single-shot statistical mechanics

The use of the von Neumann entropy in formulating the laws of thermodynamics has recently been challenged. It is associated with the average work whereas the work guaranteed to be extracted in any single run of an experiment is the more interesting quantity in general. We show that an expression that quantifies majorisation determines the optimal guaranteed work. We argue it should therefore be the central quantity of statistical mechanics, rather than the von Neumann entropy. In the limit of many identical and independent subsystems (asymptotic i.i.d) the von Neumann entropy expressions are recovered but in the non-equilbrium regime the optimal guaranteed work can be radically different to the optimal average. Moreover our measure of majorisation governs which evolutions can be realized via thermal interactions, whereas the nondecrease of the von Neumann entropy is not sufficiently restrictive. Our results are inspired by single-shot information theory.Comment: 54 pages (15+39), 9 figures. Changed title / changed presentation, same main results / added minor result on pure bipartite state entanglement (appendix G) / near to published versio

Coping with anxiety: Brain structural correlates of vigilance and cognitive avoidance

Background: Individuals differ in their dispositional coping behavior when they are confronted with anxiety-provoking situations. Cognitive avoidance is characterized by a withdrawal from threatening information, whereas vigilance denotes the intensive search for threat-related information. Functional neuroimaging studies indicate alterations in brain responsivity to emotional stimuli as a function of cognitive avoidant and vigilant coping, but findings are partially discrepant. Studies on structural correlates of coping styles are scarce. Materials and Methods: By using structural magnetic resonance imaging, the present study examined the relationship between brain gray matter volume and coping strategies in 114 healthy individuals. Individual differences in vigilance and cognitive avoidance were measured by the Mainz Coping Inventory. Results: Exploratory whole-brain analyses were conducted. Cognitive avoidant coping significantly predicted reduced gray matter volume in the bilateral thalamus, whereas vigilant coping was associated with volumetric increases in the bilateral thalamus. These relationships remained significant when controlling for a potential influence of age, sex, depressive symptoms, and trait anxiety. Discussion: Our findings indicate that dispositional strategies to deal with anxiety-provoking situations are related to volumetric alterations in the thalamus, a brain structure that has been implicated in the mediation of attentional processes and alertness, and the anticipation of harm. The dispositional tendency to monitor the environment for potential threats (i.e., vigilance), appears to be associated with volumetric increases in the thalamus, whereas the dispositional inclination to divert one’s attention away from distressing stimuli (i.e., cognitive avoidance) seems to go along with reductions in thalamic gray matter density

A natural Finsler--Laplace operator

We give a new definition of a Laplace operator for Finsler metric as an average with regard to an angle measure of the second directional derivatives. This definition uses a dynamical approach due to Foulon that does not require the use of connections nor local coordinates. We show using 1-parameter families of Katok--Ziller metrics that this Finsler--Laplace operator admits explicit representations and computations of spectral data.Comment: 25 pages, v2: minor modifications, changed the introductio

Loneliness, social support and cardiovascular reactivity to laboratory stress

Self-reported or explicit loneliness and social support have been inconsistently associated with cardiovascular reactivity (CVR) to stress. The present study aimed to adapt an implicit measure of loneliness, and use it alongside the measures of explicit loneliness and social support, to investigate their correlations with CVR to laboratory stress. Twenty-five female volunteers aged between 18 and 39 years completed self-reported measures of loneliness and social support, and an Implicit Association Test (IAT) of loneliness. The systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) reactivity indices were measured in response to psychosocial stress induced in the laboratory. Functional support indices of social support were significantly correlated with CVR reactivity to stress. Interestingly, implicit, but not explicit, loneliness was significantly correlated with DBP reactivity after one of the stressors. No associations were found between structural support and CVR indices. Results are discussed in terms of validity of implicit versus explicit measures and possible factors that affect physiological outcomes

Derivatives and Credit Contagion in Interconnected Networks

The importance of adequately modeling credit risk has once again been highlighted in the recent financial crisis. Defaults tend to cluster around times of economic stress due to poor macro-economic conditions, {\em but also} by directly triggering each other through contagion. Although credit default swaps have radically altered the dynamics of contagion for more than a decade, models quantifying their impact on systemic risk are still missing. Here, we examine contagion through credit default swaps in a stylized economic network of corporates and financial institutions. We analyse such a system using a stochastic setting, which allows us to exploit limit theorems to exactly solve the contagion dynamics for the entire system. Our analysis shows that, by creating additional contagion channels, CDS can actually lead to greater instability of the entire network in times of economic stress. This is particularly pronounced when CDS are used by banks to expand their loan books (arguing that CDS would offload the additional risks from their balance sheets). Thus, even with complete hedging through CDS, a significant loan book expansion can lead to considerably enhanced probabilities for the occurrence of very large losses and very high default rates in the system. Our approach adds a new dimension to research on credit contagion, and could feed into a rational underpinning of an improved regulatory framework for credit derivatives.Comment: 26 pages, 7 multi-part figure

RNA polymerase II stalling promotes nucleosome occlusion and pTEFb recruitment to drive immortalization by Epstein-Barr virus

Epstein-Barr virus (EBV) immortalizes resting B-cells and is a key etiologic agent in the development of numerous cancers. The essential EBV-encoded protein EBNA 2 activates the viral C promoter (Cp) producing a message of ~120 kb that is differentially spliced to encode all EBNAs required for immortalization. We have previously shown that EBNA 2-activated transcription is dependent on the activity of the RNA polymerase II (pol II) C-terminal domain (CTD) kinase pTEFb (CDK9/cyclin T1). We now demonstrate that Cp, in contrast to two shorter EBNA 2-activated viral genes (LMP 1 and 2A), displays high levels of promoter-proximally stalled pol II despite being constitutively active. Consistent with pol II stalling, we detect considerable pausing complex (NELF/DSIF) association with Cp. Significantly, we observe substantial Cp-specific pTEFb recruitment that stimulates high-level pol II CTD serine 2 phosphorylation at distal regions (up to +75 kb), promoting elongation. We reveal that Cp-specific pol II accumulation is directed by DNA sequences unfavourable for nucleosome assembly that increase TBP access and pol II recruitment. Stalled pol II then maintains Cp nucleosome depletion. Our data indicate that pTEFb is recruited to Cp by the bromodomain protein Brd4, with polymerase stalling facilitating stable association of pTEFb. The Brd4 inhibitor JQ1 and the pTEFb inhibitors DRB and Flavopiridol significantly reduce Cp, but not LMP1 transcript production indicating that Brd4 and pTEFb are required for Cp transcription. Taken together our data indicate that pol II stalling at Cp promotes transcription of essential immortalizing genes during EBV infection by (i) preventing promoter-proximal nucleosome assembly and ii) necessitating the recruitment of pTEFb thereby maintaining serine 2 CTD phosphorylation at distal regions

Dose-response relationship between ambulatory load magnitude and load-induced changes in COMP in young healthy adults

To determine the dose-response relationship between ambulatory load magnitude during a walking stress test and load-induced changes in serum concentration of cartilage oligomeric matrix protein (sCOMP) in healthy subjects.; sCOMP was assessed before and after a 30-min walking stress test performed on three test days by 24 healthy volunteers. In each walking stress test, one of three ambulatory loads was applied in a block randomized crossover design: normal body weight (BW) (100%BW = normal load); reduced BW (80%BW = reduced load); increased BW (120%BW = increased load). Knee kinematics and ground reaction force (GRF) were measured using an inertial sensor gait analysis system and a pressure plate embedded in the treadmill.; Load-induced increases in sCOMP rose with increasing ambulatory load magnitude. Mean sCOMP levels increased immediately after the walking stress test by 26.8 ± 12.8%, 28.0 ± 13.3% and 37.3 ± 18.3% for the reduced, normal or increased load condition, respectively. Lower extremity kinematics did not differ between conditions.; The results of this study provide important evidence of a dose-response relationship between ambulatory load magnitude and load-induced changes in sCOMP. Our data suggests that in normal weight persons sCOMP levels are more sensitive to increased than to reduced load. The experimental framework presented here may form the basis for studying the relevance of the dose-response relationship between ambulatory load magnitude and load-induced changes in biomarkers involved in metabolism of healthy articular cartilage and after injury